INTRODUCTION: Cytochrome P450 (CYP) plays a key role in the metabolism of coumarin anticoagulants and nonsteroidal anti-inflammatory drugs (NSAIDs). Because CYP2C9 is a genetically polymorphic enzyme, genetic variability could play an important role in the potential interaction between NSAIDs and coumarins. We investigated whether NSAIDs were associated with overanticoagulation during therapy with coumarins and evaluated the effect of the CYP2C9 polymorphisms on this potential interaction. METHODS: We conducted a population-based cohort study among patients of an anticoagulation clinic who were treated with acenocoumarol or phenprocoumon between April 1, 1991, and May 31, 2003, and whose CYP2C9 status was known. Patients were followed up until an international normalized ratio (INR) of 6.0 or greater was reached or until the end of treatment, death, or the end of the study. Proportional hazards regression analysis was used to estimate the risk of an INR of 6.0 or greater in relation to concomitant use of a coumarin anticoagulant and NSAIDs after adjustment for several potentially confounding factors. To study effect modification by CYP2C9 genotype, stratified analyses were performed for wild-type patients and patients with a variant genotype. RESULTS: Of the 973 patients in the cohort, 415 had an INR of 6.0 or greater. Several NSAIDs increased the risk of overanticoagulation. The risk of overanticoagulation was 2.98 (95% confidence interval, 1.09-7.02) in coumarin-treated patients taking NSAIDs with a CYP2C9*2 allele and 10.8 (95% confidence interval, 2.57-34.6) in those with a CYP2C9*3 allele. CONCLUSIONS: Several NSAIDs were associated with overanticoagulation. For NSAIDs that are known CYP2C9 substrates, this risk was modified by allelic variants of CYP2C9. More frequent INR monitoring of patients taking NSAIDs is warranted.
INTRODUCTION: Cytochrome P450 (CYP) plays a key role in the metabolism of coumarin anticoagulants and nonsteroidal anti-inflammatory drugs (NSAIDs). Because CYP2C9 is a genetically polymorphic enzyme, genetic variability could play an important role in the potential interaction between NSAIDs and coumarins. We investigated whether NSAIDs were associated with overanticoagulation during therapy with coumarins and evaluated the effect of the CYP2C9 polymorphisms on this potential interaction. METHODS: We conducted a population-based cohort study among patients of an anticoagulation clinic who were treated with acenocoumarol or phenprocoumon between April 1, 1991, and May 31, 2003, and whose CYP2C9 status was known. Patients were followed up until an international normalized ratio (INR) of 6.0 or greater was reached or until the end of treatment, death, or the end of the study. Proportional hazards regression analysis was used to estimate the risk of an INR of 6.0 or greater in relation to concomitant use of a coumarin anticoagulant and NSAIDs after adjustment for several potentially confounding factors. To study effect modification by CYP2C9 genotype, stratified analyses were performed for wild-type patients and patients with a variant genotype. RESULTS: Of the 973 patients in the cohort, 415 had an INR of 6.0 or greater. Several NSAIDs increased the risk of overanticoagulation. The risk of overanticoagulation was 2.98 (95% confidence interval, 1.09-7.02) in coumarin-treated patients taking NSAIDs with a CYP2C9*2 allele and 10.8 (95% confidence interval, 2.57-34.6) in those with a CYP2C9*3 allele. CONCLUSIONS: Several NSAIDs were associated with overanticoagulation. For NSAIDs that are known CYP2C9 substrates, this risk was modified by allelic variants of CYP2C9. More frequent INR monitoring of patients taking NSAIDs is warranted.
Authors: Martina Teichert; Loes E Visser; Andrė G Uitterlinden; Albert Hofman; Peter J Buhre; Sabine Straus; Peter A G M De Smet; Bruno H Stricker Journal: Br J Clin Pharmacol Date: 2011-11 Impact factor: 4.335
Authors: Maarten J Beinema; Petra H de Jong; Har J M Salden; Merel van Wijnen; Jan van der Meer; Jacobus R B J Brouwers Journal: Mol Diagn Ther Date: 2007 Impact factor: 4.074
Authors: Albert Hofman; Cornelia M van Duijn; Oscar H Franco; M Arfan Ikram; Harry L A Janssen; Caroline C W Klaver; Ernst J Kuipers; Tamar E C Nijsten; Bruno H Ch Stricker; Henning Tiemeier; André G Uitterlinden; Meike W Vernooij; Jacqueline C M Witteman Journal: Eur J Epidemiol Date: 2011-08-30 Impact factor: 8.082
Authors: Albert Hofman; Monique M B Breteler; Cornelia M van Duijn; Gabriel P Krestin; Huibert A Pols; Bruno H Ch Stricker; Henning Tiemeier; André G Uitterlinden; Johannes R Vingerling; Jacqueline C M Witteman Journal: Eur J Epidemiol Date: 2007-10-23 Impact factor: 8.082
Authors: Albert Hofman; Monique M B Breteler; Cornelia M van Duijn; Harry L A Janssen; Gabriel P Krestin; Ernst J Kuipers; Bruno H Ch Stricker; Henning Tiemeier; André G Uitterlinden; Johannes R Vingerling; Jacqueline C M Witteman Journal: Eur J Epidemiol Date: 2009 Impact factor: 8.082